Gabaergic signalling in Autism Spectrum disorders (ASD): Role of glial cells and therapeutic perspectives.

This research review looks at how brain chemistry changes during development in autism. It focuses on GABA, a brain chemical that helps control nerve activity. In autism, this chemical system doesn't develop properly, which may contribute to learning and behaviour challenges. The authors suggest that targeting this brain chemistry could lead to new treatments for autism.

This review examines GABAergic signalling disruptions in autism spectrum disorders, focusing on the developmental shift from GABA's excitatory to inhibitory effects during brain maturation. The authors discuss how altered chloride transport (via NKCC1 and KCC2 transporters) affects this critical transition, leading to disrupted network oscillations and cognitive dysfunction in ASD. The review highlights the role of glial cells (astrocytes and microglia) in regulating these processes, particularly at the axon initial segment. Brain-derived neurotrophic factor is identified as an emerging factor.

The authors propose novel therapeutic strategies targeting chloride homeostasis and GABAergic signalling to address behavioural and cognitive deficits in ASD.

Suggests targeting chloride homeostasis and GABAergic signalling could provide new therapeutic approaches for ASD. Focus on glial cell function and axon initial segment may offer specific intervention points for addressing cognitive and behavioural symptoms.

As a review paper, findings depend on quality of underlying studies. No original data presented. Sample sizes and methodological details of reviewed studies not specified in this abstract.

During postnatal development, GABA, the major inhibitory neurotransmitter in the adult brain, depolarizes immature neurons via an outward flux of chloride. This effect results from the high intracellular chloride concentration due to activity of the cation- chloride importer NKCC1. GABA induced depolarization gives rise to Giant Depolarizing Potentials (GDPs), a primordial form of coherent network oscillations involved in neuronal networks refinement. After a critical postnatal period, the increased expression of the chloride exporter KCC2, shifts GABA's action from depolarizing to hyperpolarizing, a process altered in many neurodevelopmental disorders including ASD.

The development of sharp waves ripples, a form of network oscillations implicated in memory consolidation, is controlled by GABAergic signalling at the axon initial segment (AIS). The formation and functioning of the AIS are monitored by a special subtype of microglia located at AIS axo-axonic synapses. The persistent depolarizing action of GABA beyond the critical period or its early hyperpolarizing action, as well as aberrant formation/function of AIS, lead to changes in neuronal circuits responsible for cognitive dysfunctions in ASD. In this review, considering various models of ASD, we discuss the multifaceted role of GABA, the regulation of cation-chloride cotransporters by astrocytes and microglia, the functional role of the latter in AIS, and the emerging role of brain-derived neurotrophic factor in ASD.

Accordingly, we present novel therapeutic strategies which, could reinstate a proper chloride homeostasis and GABAergic signalling in selective neuronal circuits involved in behavioural and cognitive deficits observed in ASD.